Peripheral neuropathy and myopathy

Summary The effects of variable dietary thiamine concentrations (deficient, normal, surplus) on the development of alcoholic neuromyopathy in rats exposed for 36 weeks to 10–25% (v/v) ethanol or water (control group) as the sole drinking fluid were studied by histological and electrophysiological methods.Abnormalities in the structure of the sciatic nerve (phagocytosis, myelin abnormalities, increase in nonspecific cholinesterase activity) and tibial muscles (angular atrophic fibers, group atrophy, fibre necrosis) developed more frequently in animals on diets deficient in thiamine than in animals on diets with normal or surplus thiamine, and more frequently in animals drinking alcohol and water than in those drinking water alone. No differences were observed between the different groups in the number of perivascular sympathetic nerves, in the motor nerve conduction velocities and in the muscle fibrillation potentials.Thus, thiamine deficiency, established as a significant reduction of red blood cell transketolase activity, seems to have a deleterious effect on the peripheral nerves and muscles. The effect is enhanced by the simultaneous consumption of ethyl alcohol.     

Depletion of mitochondrial DNA in HIV-1-infected patients and its amelioration by antiretroviral therapy

Mitochondrial DNA (mtDNA) of peripheral blood mononuclear cells (PBMCs) collected from Human immunodeficiency virus 1 (HIV-1)-infected patients and healthy controls were measured longitudinally using real-time polymerase chain reaction to evaluate the effects of antiretroviral agents on mtDNA synthesis in vivo and to assess the value of monitoring mtDNA in PBMCs to predict adverse events amongst these patients. MtDNA levels in PBMCs were significantly decreased in treatment-naive HIV-1-infected patients compared with healthy people. MtDNA levels were not only significantly correlated with CD4(+) T-cell count, but also inversely correlated with HIV-1 viral load. MtDNA levels in untreated patients and healthy controls were stable during the period of observation. On the other hand, amongst patients treated with regimens containing AZT/3TC or d4T/3TC, mtDNA increased during treatment and recovered to levels comparable to healthy controls. In contrast, mtDNA decreased immediately after the initiation of an AZT/ddC-containing regimen. We did not find a correlation between mtDNA levels and changes in clinical parameters. There was no significant difference in mtDNA levels between patients with and those without lipoatrophy. Furthermore, there was no obvious difference in mtDNA levels amongst those patients exhibiting signs and symptoms of peripheral neuropathy. In conclusion, the decrease in mtDNA levels in PBMCs amongst HIV-1-infected patients and its amelioration by antiretroviral therapy may suggest the influence of direct effects on mitochondria or mtDNA by HIV-1 infection. Further investigations are needed to elucidate the mechanisms contributing to decreased mtDNA and the value of mtDNA measurement in the care of HIV-1-infected individuals.     

Sclerosteosis: report of a case in a black African man

Sclerosteosis is a rare genetic disorder of bone modelling, similar to, but distinct from, van Buchem disease; it has been described almost exclusively in Afrikaners of South Africa, a white population of Dutch ancestry. Isolated cases have been reported in a girl in Japan, a boy in Spain, and in multiracial families in Brazil and USA.
Here we report a case of sclerosteosis in a black man born in Senegal. He presented with the full features of the disease: tall stature; syndactyly; nail dysplasia; massive sclerosis of the long tubular bones, the ribs, the pelvis and the skull; multiple cranial nerve involvement: optic atrophy, facial palsy and trigeminal neuralgia. Radiologic examination, visual and brainstem auditory evoked potentials, computerized tomography and magnetic resonance imaging of the skull were performed. This seems to be the first case of the disease in a black African individual, with no known relationship with Dutch ancestry.     

High incidence of pre-excitation syndrome in Japanese families with Leber's hereditary optic neuropathy

Cardiac conduction abnormalities have been reported in families with Leber's hereditary optic neuropathy (LHON). The pre-excitation syndrome, Wolff-Parkinson-White syndrome or Lown-Ganong-Levine syndrome, is reportedly common in Finns with LHON, being seen in 14 (9%) of the 163 individuals with mitochondrial DNA (mtDNA) mutations. While this syndrome is thought to be rare in other ethnic groups with LHON, the present study of 35 Japanese LHON families confirmed that it is also relatively common among Japanese families, being seen in 5 (8%) of the 63 individuals with mtDNA mutations. It remains to be determined whether the high incidence of the pre-excitation syndrome in Finnish and Japanese LHON families is due to a particular genetic composition of ethnic groups such as in Finland and in Japan, or only to a reporting bias.     

Molecular basis of congenital insensitivity to pain with anhidrosis (CIPA): Mutations and polymorphisms in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor

Congenital insensitivity to pain with anhidrosis (CIPA), also referred to as hereditary sensory and autonomic neuropathy type IV (HSAN‐IV), is an autosomal recessive hereditary disorder characterized by recurrent episodic fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self‐mutilating behavior, and mental retardation. The TRKA (NTRK1) gene located on chromosome 1 (1q21‐q22), consists of 17 exons and spans at least 23 kb. TRKA encodes the receptor tyrosine kinase (RTK) for nerve growth factor (NGF) and is the gene responsible for CIPA. Defects in NGF signal transduction at the TRKA receptor lead to failure to support survival of sympathetic ganglion neurons and nociceptive sensory neurons derived from the neural crest. Thirty‐seven different TRKA mutations, identified in patients in various countries, including nine frameshift, seven nonsense, seven splice, and 14 missense mutations, are distributed in an extracellular domain involved in NGF binding, as well as in the intracellular signal‐transduction domain. Extensive analysis of CIPA mutations and associated intragenic polymorphisms should facilitate detection of CIPA mutations and aid in the diagnosis and genetic counseling of this painless but severe genetic disorder with devastating complications. In addition, naturally occurring TRKA missense mutations with loss of function provide considerable insight into the structure–function relationship in the RTK family. Further, molecular pathology of CIPA would provide unique opportunities to explore critical roles of the autonomic sympathetic nervous system as well as peripheral sensory nervous system that transmit noxious stimuli in humans. Hum Mutat 18:462–471, 2001. © 2001 Wiley‐Liss, Inc.     

Reactivity of human monoclonal IgM with nerve glycosphingolipids.

We examined the reactivity of monoclonal IgM of sera from patients with neuropathy and monoclonal IgM, with or without antibody activity to myelin-associated glycoprotein (MAG), as well as sera from non-neurologic patients with Waldenström's macroglobulinaemia, with various nerve glycolipids extracts or with purified gangliosides. As expected from previous studies, all (five cases) anti-MAG IgM stained two glycolipids, the chemical characteristics of which corresponded to sulphated glucuronyl-paragloboside (SGPG) and sulphated glucuronyl-lactosaminyl-paragloboside (SGLPG). Five of 12 sera from patients with neuropathy whose IgM was devoid of anti-MAG reactivity stained nerve extracts greatly enriched (98%) with SGPG and SGLPG. Three of these five sera reacted with additional glycolipids and/or gangliosides. Two of 16 sera from patients with macroglobulinaemia without neuropathy reacted strongly with both SGPG and SGLPG. The latter finding as well as the detection of low titre of anti-sphingolipid antibodies in normal sera may cast a doubt on the pathogenetic significance of this antibody activity.     

Right-left correlation of the sympathetically induced fluctuations of photoplethysmographic signal in diabetic and non-diabetic subjects

Photoplethysmography (PPG) records the cardiac-induced changes in tissue blood volume by light-transmission measurements. The baseline and amplitude of the PPG signal show very low-frequency (VLF) spontaneous fluctuations, which are mediated by the sympathetic nervous system, and high correlation between right and left extremities of healthy subjects. As sympathetic neuropathy is one of the diabetic complications, the right-left correlation of the PPG fluctuations was examined in diabetic patients. The PPG signal was simultaneously measured in the two index fingers and the two second toes of 35 diabetic patients and 33 non-diabetic subjects. For each PPG pulse, the baseline and amplitude were determined, and the right-left correlation coefficients of the VLF fluctuations in the baseline and amplitude were derived. The VLF fluctuations in the baseline showed high right-left correlation, both for fingers (0.93±0.05) and toes (0.93±0.06), for the non-diabetic subjects, and significantly lower correlation (0.78±0.22 and 0.84±0.17, respectively) for the diabetic patients. Similar results were obtained for the amplitude VLF fluctuations. The right-left correlation coefficients for diabetic patients decreased with the disease duration for the toe baseline and toe amplitude fluctuations and correlated with heart rate response to deep breathing for the finger baseline and toe amplitude fluctuations. The right-left correlation coefficients of the PPG fluctuations provide a simple and convenient means for assessing the adequacy of the sympathetic nervous system function.     

Lectin binding and desmin expression during necrosis, regeneration, and neurogenic atrophy of human skeletal muscle

Changes in the cytoplasm of skeletal muscle fibres during necrosis, regeneration, and neurogenic atrophy have been studied in a wide range of human neuromuscular diseases with a panel of eleven biotinylated lectins and by immunohistochemical staining for the cytoskeletal protein desmin. Increased binding of several lectins was observed in both necrotic and regenerating fibres, with Concanavalin A the most consistently positive lectin. Staining for desmin was strong in the cytoplasm of regenerating and partially damaged fibres and was lost in necrotic fibres, although there were differences in the staining reactions of the two antidesmin antibodies used. In fibres which had undergone neurogenic atrophy, cytoplasmic lectin binding was seen only with Griffonia simplicifolia 1 lectin, and desmin was expressed more strongly than in normal fibres. Lectin binding and immunohistochemical staining from desmin can supplement the information obtained from muscle biopsies by conventional histochemical methods and lead to a better understanding of the mechanisms of muscle damage.     

Screening for the two most frequent mutations in Leber's hereditary optic neuropathy by duplex PCR based on allele-specific amplification

This report describes a rapid and inexpensive assay, which allows detection, in whole blood and by PCR alone, of the two most frequent mitochondrial DNA mutations causing Leber's hereditary optic neuropathy. The assay is based on allele-specific amplification, using primers with the mutation-specific base in the 3′ position, and a deliberately introduced G→C Substitution of base no. four from the 3′ end, which prevents amplification of the wild-type allele. © 1993 Wiley-Liss, Inc.     

Brachytelephalangic chondrodysplasia punctata in an extremely premature infant

We report on 3 sibs (2 males and one female) with sensorineural deafness. The presence of ovarian dysgenesis in the girl suggested a diagnosis of Perrault syndrome. In addition our patients have a sensory polyneuropathy and amelogenesis imperfecta. Two of the patients have mild mental retardation, fine choreatic movements, and dyspraxia. It is discussed whether these findings are part of a separate clinical entity or should be included within the spectrum of the Perrault syndrome. © 1994 Wiley-Liss, Inc.